Staphylococcus aureus infects more than 1.2 million patients per year in U.S. hospitals. The tremendous success of S. aureus as a pathogen is in part due to the expression of an arsenal of exoproteins. The effects of different host environments on the global expression of S. aureus exoproteins are not completely understood. One environmental cue that S. aureus likely senses in vivo is fluctuations in iron availability. The central hypothesis of this application is that S. aureus senses changes in iron availability during infection to coordinate a specific exoprotein expression profile that facilitates bacterial survival. This hypothesis is supported by the preliminary data presented here, which demonstrate that S. aureus differentially coordinates the expression of cytotoxins and immunomodulatory proteins in response to changes in iron availability. The goals of this application are to determine the molecular mechanisms by which S. aureus sensically, we will investigate the role of Staphylococcal Superantigen-like exotoxins (Ssl) in S. aureus-host interactions using a combination of animal models and ex vivo primary culture models of infection. Aim two is designed to identify the regulatory system(s) responsible for iron-dependent regulation of exoproteins and to delineate the role of this system(s) in S. aureus pathogenesis. We will apply a combination of DNA binding assays, transposon screens, and microarrays to facilitate the identification and characterization of the molecule(s) responsible for the iron-dependent expression of S. aureus exoproteins. Furthermore, we will determine the contribution of the iron-sensing system(s) to S. aureus pathogenesis and to the in vivo expression of iron-regulated exoproteins. RELEVANCE: The proposed research will investigate how S. aureus senses host environments to regulate the expression of exoproteins and the function of these exoproteins in S. aureus pathogenesis. Understanding how S. aureus coordinates the expression of virulence factors during infection and the effects of these factors on the host may uncover targets for the generation of novel therapeutics against this important human pathogen. 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